Lyme disease is caused by infection with the tick-transmitted spirochete Borrelia burgdorferi. Infection in humans can cause inflammatory arthritis in approximately 60% of those not treated at the time of the tick bite, and this can progress to chronic disease in a small percentage of susceptible individuals. The infection-associated arthritis can be studied in mice; with strong evidence suggesting that the severity of B. burgdorferi induced arthritis is regulated by the genetics of the host. Using intercross populations of mice developed by crossing inbred strains that develop severe Lyme arthritis (C3H) with those that display milder arthritis (C57BL/6), we have identified six Quantitative Trait Loci (QTL) that regulate arthritis severity. These QTL are highly significant, with LOD scores ranging from 3.5-10.2. Congenic lines have been developed to isolate individual chromosomal intervals associated with QTL by backcrossing seven generations to the reciprocal parent. Several interval specific congenic lines with highly penetrant Lyme arthritis phenotypes have been generated. The goals of this application are to 1) complete the characterization of the C3H x C57BL/6 congenic lines and develop interval specific recombinant lines to narrow the physical region associated with each QTL to that amenable to positional cloning; 2) determine if Ncf1, a component of the phagocyte NADPH oxidase, is a candidate for a highly significant QTL mapping to chromosome 5 (Bb2); and 3) determine the mechanism by which reactive oxygen intermediates suppress B. burgdorferi-induced arthritis in mice. These studies will provide information on the genetic regulation of Lyme arthritis, with the ultimate goal being the identification of polymorphic genes responsible for differences in severity in mice and humans. Studies with a strong candidate gene, Ncf1, have further revealed an unexpected paradigm in inflammatory regulation, suggesting that reactive oxygen intermediates may play a regulatory role in Lyme arthritis.